Clinical Trial: Pharmacokinetic and in Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD Normal and G6PD Deficiency

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Open Label Randomized Controlled Trial Pharmacokinetic and Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD

Brief Summary: The emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thai border and more recently on the Myanmar-Thai border jeopardizes the renewed global efforts of control and elimination of malaria. Containment of this severe threat requires reduction of transmission of the resistant phenotype by adding gametocytocidal drugs to the treatment of falciparum malaria. Mathematical models also predict that transmission blocking will be required if the goal of malaria elimination is to be achieved. The only drug currently available with strong gametocytocidal properties against the more mature gametocytes is primaquine. However, the oxidative properties of primaquine readily causes acute haemolysis in glucose 6 phosphate dehydrogenase (G6PD) deficiency, the degree of which appears to be inversely related to G6PD enzyme activity. Because of these safety concerns, primaquine is not widely deployed in treatment regimens for falciparum malaria, even in areas with documented artemisinin resistance. Methylene blue, which does not exert its action through an oxidative mechanism, is a promising alternative as a gametocytocidal adjuvant to artemisinin combination therapies (ACTs). Paul Ehrlich discovered methylene blue as the first synthetic drug ever to treat malaria. In contrast with primaquine, the thiazine dye methylene blue asserts its properties as an oxidizing agent only at very high doses, whereas at pharmacologic doses it has reducing agent properties and is for this reason used as a medication for the treatment of methemoglobinemia. A recent laboratory study identified methylene blue as a potent inhibitor of gametocyte development across all stages, almost fully abolishing P. falciparum transmission to mosquitoes at concentrations readily achievable in humans. In addition, a recent clinical study in 180 children with uncomplicated falciparum malaria in Burkina Faso showed that, compared to artesunate-amodiaquine alone, addition of the cheap drug

Detailed Summary:
Sponsor: University of Oxford

Current Primary Outcome:

  • Pharmacokinetic profile of Primaquine [ Time Frame: 7 days ]
    Maximum concentration (Cmax), Area under the concentration curve (AUC 0-24), Elimination rate constant (PRQ-λz), and Elimination half life (t1/2) for primaquine when given standard dose in G6PD normal and G6PD deficiency
  • Pharmacokinetic profile of Carboxyprimaquine [ Time Frame: 7 days ]
    Maximum concentration (Cmax), area under the concentration curve (AUC 0-24), elimination rate constant (PRQ-λz), and elimination half life (t1/2) for carboxyprimaquine (primaquine metabolite) when given standard dose in G6PD normal and G6PD deficiency
  • Pharmacokinetic profile of Methylene blue [ Time Frame: 7 days ]
    Maximum concentration(Cmax), area under the concentration curve (AUC 0-24) elimination rate constant (MB-λz), and elimination half life (t1/2) for methylene blue when given standard dose in G6PD normal and G6PD deficiency
  • Oocysts production in mosquitoes [ Time Frame: 7 days ]
    Reduction of oocysts production in mosquitoes fed with gametocytes which were exposed to methylene blue and primaquine
  • Methaemoglobin, Hematocrit and Hemoglobin levels [ Time Frame: 7 days ]
    Methaemoglobin, hematocrit and hemoglobin level when given primaquine and methylene blue in G6PD normal and G6PD deficiency


Original Primary Outcome: Same as current

Current Secondary Outcome: Safety of Primaquine and Methylene Blue [ Time Frame: 1 month ]

Safety and tolerability parameters, including adverse events, clinical laboratory, and vital signs assessments


Original Secondary Outcome: Same as current

Information By: University of Oxford

Dates:
Date Received: August 1, 2012
Date Started: July 2013
Date Completion:
Last Updated: November 2, 2015
Last Verified: November 2015